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Thus, natural compounds with anti-cancer properties and lower systemic toxicity, such as gallic acid (GA), have been explored as alternatives. However, GA\u2019s therapeutic effects are limited due to its rapid metabolism, low bioavailability, and low permeability across the blood\u2013brain barrier (BBB). This work aimed to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with folic acid (FA), as its receptor is overexpressed in BBB and GBM cells, for GA delivery to enhance its therapeutic efficacy. The preparation of NPs was optimized by a central composite design (CCD). The obtained NPs showed physicochemical features suitable for drug internalization in BBB and tumor cells (sizes below 200 nm, monodispersity, and negative surface charge) and the ability to maintain a slow and sustained release for 40 days. In vitro studies using a human GBM cell line (U215) revealed the NPs\u2019 ability to accumulate in the target cells, further promoting GA antiproliferative activity by inducing the production of intracellular reactive oxygen species (ROS). Furthermore, GA encapsulation in the developed nanosystems conferred higher protection to healthy cells.<\/jats:p>","DOI":"10.3390\/polym16152161","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T08:51:42Z","timestamp":1722329502000},"page":"2161","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Folic-Acid-Conjugated Poly (Lactic-Co-Glycolic Acid) Nanoparticles Loaded with Gallic Acid Induce Glioblastoma Cell Death by Reactive-Oxygen-Species-Induced Stress"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-7520","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Ramalho","sequence":"first","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Alves","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6918-8775","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Andrade","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7780-0901","authenticated-orcid":false,"given":"Jorge","family":"Lima","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, R. Alfredo Allen, 4200-135 Porto, Portugal"},{"name":"Ipatimup\u2014Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Faculty of Medicine, University of Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-3967","authenticated-orcid":false,"given":"Joana Ang\u00e9lica","family":"Loureiro","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-3432","authenticated-orcid":false,"given":"Maria Carmo","family":"Pereira","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jov\u010devska, I. 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